Relay Compound Research Articles

Synthesis of 1,3-Diols by O-Nucleophile Additions to Activated Alkenes

The diastereoselective synthesis of 1,3-diols by addition of oxygen nucleophiles to activated alkenes is presented. This review focuses on homoallylic alcohol substrates that react with a relay compound to form an intermediate oxygen nucleophile, which in turn will lead to a protected 1,3-diol by intramolecular addition to the olefin moiety.1 Introduction2 Base Catalysis3 Organocatalysis4 Activation with Non-Metallic Electrophiles5 Activation with Transition Metal Derivatives6 Conclusions

Enantioselective Palladium‐Catalyzed N‐Allylation of Lactams

AbstractN‐Deprotonated five‐, six‐, seven, and nine‐membered lactams undergo smooth palladium‐catalyzed N‐allylation with methyl‐(pent‐3‐en‐2‐yl)‐carbonate or 2‐chloro‐3‐pentene. With axially chiral bisphosphane ligands, enantioselectivities ranging from 83 to 97% ee are reached. The configuration of one of the allylation products is assigned unambiguously by the preparation of a relay compound and by analogy to the others. Using the enantioselective allylation protocol as a key step, δ‐valerolactam is converted into (4S,9aR)‐4‐methylquinolizidine.

Efficient Construction of Pyrano[3,2‐a]carbazoles: Application to a Biomimetic Total Synthesis of Cyclized Monoterpenoid Pyrano[3,2‐a]carbazole Alkaloids

We have developed a highly efficient route to 2-hydroxy-3-methylcarbazole (1) via a palladium-catalyzed construction of the carbazole skeleton. Using 1 as relay compound, different methods for annulations of pyran rings by reaction with terpenoid building blocks have been tested. The Lewis acid promoted reaction of 1 with prenal (21) opened up an efficient route to girinimbine (3) and the corresponding reaction with citral (25) afforded mahanimbine (5). Oxidation of compounds 3 and 5 provided murrayacine (4) and murrayacinine (6). Following the biogenetic proposal, mahanimbine (5) has been exploited for efficient biomimetic syntheses of the cyclized monoterpenoid pyrano[3,2-a]carbazole alkaloids cyclomahanimbine (7), mahanimbidine (8) and bicyclomahanimbine (9). The interconversions of 5, 7, 8 and 9 are described and mechanistic implications are discussed. Structural assignments are unambiguously verified by X-ray crystal structure determinations. Moreover, cyclomahanimbine (7) was transformed into murrayazolinine (10) and exozoline (11).

Chemical Confirmation of the Structure of a Mutagenic Aminophenylnorharman, 9-(4’-Aminophenyl)-9H-pyrido[3,4-b]indole: An Authentic Synthesis of 9-(4’-Nitrophenyl)-9H-pyrido[3,4-b]indole as Its Relay Compound

9-(4'-Aminophenyl)-9H-pyrido[3,4-b]indole 2 is a mutagenic compound produced by non-mutagenic norharman 1 and aniline in the presence of S9 mix. 9-(4'-Nitrophenyl)-9H-pyrido[3,4-b]indole 4, the relay compound for synthesis of 2, was synthesized starting from ethyl indole-2-aldehyde 12 via initial N-(4-nitro)phenylation of the indole nucleus, elongation of the 2-aldehyde substituent, and then construction of the pyridine nucleus in order to ensure the nitrogen substitution in 2.

13C-labeled bilirubin: synthesis of 31(32),171(172)-di-[13C]-mesobilirubin-XIIIα

The title compound, labeled with 13C in the ethyl groups was synthesized from K13CN and low-molecular-weight components. The synthetic relay compound was 31(32)[13C]-xanthobilirubinic acid methyl ester in a synthetic route that leads to a label in the ethyl β-substituent of a dipyrrinone model for bilirubin. This labeled dipyrrinone was oxidatively coupled to the dimethyl ester of mesobiliverdin-XIIIα, thereby providing a route to a 13C-labeled mesobiliverdin and mesobilirubin, with one carbon of each ethyl being 98% 13C-enriched.

Acid‐Induced and Reductive Transfor­mations of Enantiopure 3,6‐Dihydro‐2H‐1,2‐oxazines – Synthesis of Dideoxyamino Carbohydrate Derivatives

AbstractAcid‐catalyzed transformations of carbohydrate‐derived 3,6‐dihydro‐2H‐1,2‐oxazines such as 1, 5 and 13 provided a set of enantiopure furano‐1,2‐oxazines or pyrano‐1,2‐oxazines. The reaction conditions determined the degree of solvolysis of the compounds. An X‐ray analysis of product 6 revealed an interesting network of hydrogen bonds. Reductive cleavage of the N–O bond of the 1,2‐oxazines either by hydrogen/palladium or by samarium diiodide furnished enantiopure aminofuran and ‐pyran derivatives, e.g. 9 and 11 or compound 16, which can be regarded as protected 4‐amino‐1,4‐dideoxyhex‐3‐ulose or 4‐amino‐1,4‐dideoxyoct‐3‐ulose derivatives. We thus have established a short and stereocontrolled route to amino carbohydrate derivatives with 1,2‐oxazines as crucial relay compounds. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

1,2- O-Isopropylidene-5-alkene templates for the synthesis of oligo-tetrahydrofurans

The highly functionalized THF 4 was prepared in eight steps from 2,5-cyclooctadiene. The key step in this synthesis was a novel desymmetrization reaction involving the iodoetherification of the C2 symmetric bis-isopropylidene alkene 6 to THF 4 . The versatility of 4 was demonstrated by its conversion to bis-THF 3 , a known precursor for trilobacin, and to the tris-THF-lactone 5 , a potential relay compound for cyclic polyether analogues.

Effects of valproate derivatives II.: Antiepileptic efficacy in relation to chemical structures of valproate sugar esters

The structure effect relationships of derivatives of the antiepileptically active ester of valproate (VPA) 3,4:5,6-Di- O-isopropylidene-1- O-(2-propylpentanoyl)- d-mannitol ( 1) have been studied using intracellular recording to record the membrane potential of single neurons (buccal ganglia, Helix pomatia). Epileptiform activity was induced by the epileptogenic drug pentylenetetrazol. The effects of several derivatives on epileptiform activity were compared with those of the relay compound 1. Most of the synthesized agents decreased the duration of paroxysmal depolarization shifts (PDS) and increased their repetition rate. It was considered that a decreased the duration of PDS is antiepileptic and an increased repetition rate is pro-epileptic. Compared with the effects of compound 1, the following relationships were found: (1) Derivatives containing glucitol or galactitol were of similar antiepileptic potency. (2) Introduction of pyranoses or furanoses rendered the substances inactive or even pro-epileptic. (3) VPA in position 1 and 6 at the sugar acted as an antiepileptic whereas in position 3 and 4 it proved to be ineffective. (4) Replacement of VPA by ethylhexanoyl reduced the antiepileptic potency slightly and pivaloyl strongly. (5) Replacement of isopropylidene bridges by penta- O-acetyl or cyclohexylidene residues led to largely inactive substances. (6) Compounds having isopropylidene bridges in position 2,4;3,5 proved to be antiepileptic whereas bridges especially in positions 2,3:4,5 slightly enhanced epileptic activities.

Toward a Total Synthesis of the Immunosuppressant Sanglifehrin A. Preparation of Two Relay Compounds by Degradation and Their Use in the Reassembly of the Natural Product

A potential relay route for the synthesis of the novel immunosuppressive agent sanglifehrin A (1) has been developed. Degradation of 1 by a sequence involving regioselective dihydroxylation of the C26,C27 double bond, followed by periodate cleavage of the resulting diol 4, afforded lactol 2 and macrocyclic aldehyde 3. Intramolecular ketal formation between the 1,3-diol and ketone functions present in 3 gave ketal−aldehyde 5. Lactol 2 was converted into sulfone 14 in four steps. The fragments 5 and 14 were reassembled, using the Julia−Kocienski olefination procedure, to afford intermediate 15, which was converted back to sanglifehrin A (1) after two deprotection steps.

A novel desymmetrization reaction of an acetogenin precursor: A formal synthesis of trilobacin and asimicin

A two-directional strategy which is based on the haloetherification reaction of a bis-5,6-O-isopropylidene alkene, is applied to the synthesis of a versatile relay compound for the bis-THF containing acetogenins.

An approach to the A/B substructure of 11(15→ 1)-abeotaxanes. A formal synthesis of compressanolide

Abstract Preparation of highly functionalized 16 constitutes one of the first attempts at the synthesis of the A/B carbon skeleton of the 11(15→1)-abeotaxanes. Further transformations of labile 16 give enedione 17 , an important relay compound in the synthesis of guaianolide compressanolide.

Preparation of alkyl-substituted indoles in the benzene portion. Part 15. Asymmetric synthesis of (+)-duocarmycin SA using novel procedure for preparation of hydroxyindoles.

An asymmetric total synthesis of natural (+)-duocarmycin SA (1) starting from L-malic acid (7) was achieved as shown in Chart 5, establishing firmly the absolute configuration of 1. In order to find suitable reaction conditions for the key step, i.e., the formation of an alkoxyindole derivative, model compounds 9 and 40 were synthesized and two acetalization conditions using i) 2-ethyl-2-methyl-1,3-dioxane and boron trifluoride etherate, and ii) 1,3-bis(trimethylsilyloxy)propane and trimethylsilyl triflate were found to be effective. The former conditions were successfully applied to total synthesis and 49b was prepared from 48 in 54% yield. Further elaborations including i) Curtius rearrangement of 53b to 56, and ii) cleavage of the primary benzyloxy group in the presence of the secondary one in its close vicinity (56-->57) led to the relay compound 62, whose conversion to 1 has already been accomplished.

Synthesis of Duocarmycin SA by Way of Methyl 4-(Methoxycarbonyl)oxy-3H-pyrrolo[3,2-f] quinoline-2-carboxylate as a Tricyclic Heteroaromatic Intermediate.

Formal syntheses of (±)-duocarmycin SA, natural (+)-duocarmycin SA and unnatural (-)-duocarmycin SA were accomplished by way of a tricyclic heteroaromatic compound 10b. For the preparation of 10, an N-oxide route aiming at a process 20 in Chart 3 was first investigated by synthesizing 19, derived from Stille coupling products 13 between bromopyrrole 7a and 3-(tributylstannyl)pyridines 12, but without success. As the second approach, Stille coupling products 9a-c were prepared by condensation between 7a and 2-substituted 3-(trialkylstannyl)pyridines 8a-f. Both 9b and 35, derived from 9c, were converted to their silyl enol ethers and then subjected to a palladium-catalyzed methyl ketone-arylation reaction in the presence of tributyltin fluoride and lithium chloride, affording 10a and 10b in excellent yields, especially from 35. Application to 10b of three successive operations, i.e., i) partial reduction of 10b to dihydropyridine derivatives 11a and 11b, ii) dihydroxylation of the double bonds formed to give 58 and 59, and iii) reductive elimination of the hydroxy groups adjacent to the nitrogen function and the aromatic ring, afforded 6 in fairly good yield. Compound 6 was readily converted to relay compounds 64 and 67, completing total syntheses of (±)-, (+)-, and (-)-duocarmycin SA. Both Sharpless asymmetric dihydroxylation (AD) and Jacobsen's asymmetric epoxidation were applied to 11a and 11b. At the best, 81% ee was observed in the AD reaction of 11a using 2, 5-diphenyl-4, 6-bis(9-O-dihydroquinyl)pyrimidine [(DHQ)2PYR], but the resulting 58 possessed an unnatural absolute configuration.

ChemInform Abstract: Total Synthesis of Zaragozic Acid A (Squalestatin S1) (I). Degradation to a Relay Compound (II) and Reassembly of the Natural Product.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Total synthesis of natural (+)-FR900482. 1. Synthetic and end-game strategies

A synthetic strategy for natural (+)-FR900482 ( 1) was developed by featuring a convergent and enantioselective sequence which commences with 5-hydroxyisophthalic acid and L-diethyl tartrate. The proposed key intermediate 4 was synthesized starting from FK973, the triacetyl derivative of 1, and successful reconversion of 4 into 1 was also achieved. These preliminary studies definitely demonstrated that 4 is suitable as a potential relay compound toward 1 and that the crucial final sequence of reactions ( 4→1 ) involving delicate deprotection and oxidation steps can be realized.

Total Synthesis of Zaragozic Acid A (Squalestatin S1). Degradation to a Relay Compound and Reassembly of the Natural Product

Zaragozic acid A (squalestatin S1) (1) was converted into the simpler derivative 2, which was reconverted into the natural product, thus establishing 2 as a viable relay compound for total synthesis of 1. The degradation (Scheme 1) consisted of formation of the tri-tert-butyl ester (3), from which the two side chains were sequentially removed to obtain 8. Aldehyde 8 was converted into dimethyl acetal 2 in standard fashion. The C6 acyl side chain 14 was prepared from (S)-2-methylbutanol (“active amyl alcohol”), and the desired 4S configuration was obtained by use of Evans asymmetric enolate methylation (Scheme 2). The C1 alkyl side chain was prepared as stannane 23a from (R)-2-methyl-3-phenylpropanol (21) as shown in Scheme 5. For conversion of 2 back into zaragozic acid A, the dimethyl acetal was first converted into the cyclic acetal 17, thus protecting the C7 hydroxyl group. The remaining hydroxyl group was then acylated with acid 14 to obtain 18, which was transformed into aldehyde 20 (Scheme 4). The C1 alkyl chain was elaborated by the addition of a chiral α-alkoxyorganocerium reagent, obtained from 23a, to aldehyde 20. The resulting mixture of diastereomeric secondary alcohols was converted into zaragozic acid A (1) in six steps (Scheme 6).

Light-induced hydrogen production using waste compounds as sacrifical electron donors

Systems for the conversion and chemical storage of solar energy are usually based on photo-induced electron transfer reactions from an excited sensitizer to an electron acceptor (i.e. an electron relay compound). We have investigated the photo- and electrochemical properties of two novel electron relay compounds: l,l″,r″′-trimethyl[4,2′; 4′,4″; 6′,4″′]quaterpyridinium trichloride (1) and 1,1′,1″,1″′-tetramethyl[4,2′; 4′,4′’; 6′,4″] quaterpyridinium tetrachloride (2). When solutions containing Ru(bpy)3Cl2 or Zn-porphyrin (as photosensitizer), compound1 or2 and EDTA (as sacrificial electron donor) are irradiated by visible light (λ > 400 nm), only the formation of reduced relay compound 1 occurs. Addition of platinum catalyst to such solutions with compound 1 leads to the formation of hydrogen. Quantum yields are in the range of 5%, calculated for absorbed light. Using other sacrificial electron donors such as alcohols or glucose (or waste compounds like 4-chlorophenol) did not result in hydrogen evolution. However,1 and2 are reduced by these sacrificial electron donors in the absence of an additional photosensitizer, when near UV irradiation light (λ > 280 nm) is used. Quantum yields for hydrogen production with compound1 are about 2%, calculated for absorbed light out of GC-measurements from H2 in the gas phase above the irradiated solution. The photo- and electrochemical properties of compounds1 and2 are discussed.

Synthesis of strychnine and the Wieland-Gumlich aldehyde

The tetracyclic amine 9 was converted through several steps into secondary amine 13 and acetylated with (phenylthio)acetic acid activated by bis(2-oxo-3-oxazolidinyl)phosphinic acid to give amide 15. Treatment of 15 with sodium hydride in tetrahydrofuran at 25 o C resulted in rapid conversion into a single diastereomer, 16. This same conjugate addition has been conducted at the sulfoxide oxidation level and also with a chiral sulfoxide to provide optically active compounds (Scheme VI). Conversion of sulfoxide 19 into dione 27 followed by ketalization and reduction gave tertiary amine 34. Deprotection and oxidation with mercuric acetate gave the core strychnine skeleton 36. The β-aminoacrylate double bond in 36 was reduced to give 39 followed by epimerization to give 40. Ester 40 was protected as the sulfonamide derivative 44, and the ester was reduced to give 45. Alcohol 45 undergoes normal acid hydrolysis to give hemiketal 47. The Wieland-Gumlich aldehyde 48 was converted into the relay compound by the route shown in scheme XI, thus providing a convenient correlation and short route to 47. Hemiketal 47 was converted into ketone 52 and treated with (EtO) 2 P(O)CH 2 CN/ KN(SiMe 3 ) 2 /THF at 25°C to give the two geometrical isomers 53 (E) and 54 (Z) in a ratio 3:2. The incorrect stereoisomer could be recycled by irradiation in benzene to give a mixture of 53 and 54. Reduction of 53 gave the required allylic alcohol 55. Desilylation of 55 gave diol 56. The synthesis of strychnine and the Wieland-Gumlich aldehyde was completed by selective silylation of the allylic hydroxyl group in 56 and oxidation to give the unstable aldehyde 58. Desilylation of 58 gave the protected Wieland-Gumlich aldehyde 49, which was deprotected by treatment with sodium anthracenide to give 48

Photoinduced hydrogen production in dilute solutions and organized assemblies

A new class of covalently linked cyanine dye-electron relay compounds have been investigated. As well as 2-[1-ethyl-1,2-dihydro-chinolinyliden-(2)-methyl]-1-ethyl-chinolinium chloride (1), 1-[3-[2-[(1-ethyl-2(1H)-chinolinyliden)methyl]chinolinium-1-yl]propyl]-1′-methyl-4,4′-bi-pyridinium trichloride (2) and 1-[3-[2-[(1-ethyl-2(1H)-chinolinyliden)methyl]chinolinium-1-yl]pentyl]-1′-methyl-4,4′-bipyridinium triiodide (3) were able to form huge molecular associates with a well-defined three-dimensional structure in dilute, aqueous solutions (critical gel concentration ccrit > 2 × 10−3mol 1−1). Photochemical properties of compounds (1)-(3) were different in gels and in solutions (c < ccrit) without organized dye associates. Owing to antenna effects, organized assemblies provide an intense light harvesting effect. Covalently linked viologen groups quench the excited dye intramolecularly with a higher efficiency. Furthermore, the increased quenching efficiency was found to be dependent on the degree of organization. In dilute aqueous solutions (c < ccrit, λEX > 280 nm), compounds (1)-(3) could act as photosensitizers for light-induced hydrogen production (via intermolecular charge separation) with quantum yields of φ12H2 = 2%. In organized assemblies (c >ccrit), intramolecular charge separation [in compounds (2) and (3)] could be observed and hydrogen production experiments were performed successfully.

New sensitizing relay compounds for H2 production

Abstract Hydrogen producing systems, which consist of a photosensitizer (like Ru(bipy)3Cl2), an electron relay (e.g. methyl viologen), a colloidal catalyst (platinum) and a sacrificial electron donor (EDTA) are well known. We have investigated new electron relay substances (1,1″, 1′″-trialkyl [4,2′;4′,4″;6′,4″′] quaterpyridinium trichloride and related compounds), which combine the features of the sensitizer and the electron relay. The maxima of light absorption of these compounds were in the u.v. range, at about 320 nm. The fluorescence of the relay compounds decreased with increasing relay concentration (self-quenching). We have determined the quantum yields of the systems (containing the electron relay, EDTA, platinum catalyst and acetate buffer) by exciting these solutions with near-u.v. light (high-pressure Hg lamp, λ > 280 nm, for the calculations the number of incident photons with λ > 280 nm, but only hydrogen in the gas phase ( 1 2 H 2 ) was taken into account). The quantum yields were in the region of about 2%. Furthermore, we found that only electron relay compounds which have a pyridinium ring with a free electron pair were capable of producing hydrogen without dye stuff. The reaction mechanism is discussed in detail.